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Sunday, 3 July 2016

Lipid Biomarkers (cholesterol, lipoproteins) and Cancer Risk

Lipid biomarkers are frequently used to assess the risk of heart disease. A simple blood test provides information about LDL-cholesterol (LDL-C) (1), commonly nicknamed the bad cholesterol and HDL-cholesterol (HDL-C) (2), often called the good cholesterol. Triglycerides are usually measured as well (3).

For many different reasons, lowering LDL-C has become a primary target for the prevention of heart disease. Evidence suggests a relationship between LDL-C and the risk of coronary heart disease. Lifestyle measures that lower LDL-C are usually recommended, and statins (cholesterol-lowering drugs) are used by millions of people worldwide to lower LDL-C.

Blood levels of triglycerides are also associated with the risk of heart disease (4). Furthermore, there is an inverse correlation between HDL-C and cardiovascular risk. Hence, high HDL-C levels are associated with less risk of heart disease, and low levels are related to increased risk.

But, what about the relationship between lipid biomarkers and cancer? Do we find the same pattern there?

Cancer is the second leading cause of death in most western countries. Diet, smoking, and obesity are known risk factors for cancer. These risk factors often correlate with alterations in blood lipid markers.

Lipid Biomarkers

Because fats are insoluble in water, cholesterol and triglycerides cannot be transported in blood on its own. Instead, cholesterol is attached to hydrophilic proteins that function as transport vehicles carrying different types of fats such as cholesterol and triglycerides. These combinations of fats and protein are termed lipoproteins. The lipoprotein particles vary in the primary lipoprotein present and the relative contents of the different lipid components.

The lipoproteins are classified according to their chemical properties. There are five major types; chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

Measuring the amount of cholesterol carried by the different types of lipoproteins has become standard practice. Thus, LDL-C reflects the amount of cholesterol carried by LDL and HDL-C reflects the amount off cholesterol carried by HDL.

However, measuring the concentration of the lipoproteins themselves may be more informative than measuring the amount of cholesterol within these particles. There is substantial evidence that some lipoproteins play a fundamental role in heart disease and their interaction with the arterial wall appears to initiate the cascade of events that leads to atherosclerosis. Lipoproteins that promote atherosclerosis and cardiovascular disease are termed atherogenic. Apolipoprotein B (apo B) is a major component of atherogenic lipoproteins (5).

Apo B occurs in 2 main forms, apo B-48, and apo B-100. Apo B-48 is mainly synthesized by the small intestine and is primarily found in chylomicrons. Apo B-100 is the protein found in lipoproteins synthesized by the liver. From the viewpoint of cardiovascular risk, apo B-100 is the important one.

Apo B-100 is the primary lipoprotein in LDL (6) and other lipoproteins that promote atherosclerosis, such as VLDL and lipoprotein(a) (7).

Apolipoprotein A-I (Apo A-I) is the main protein component of HDL. As with HDL-C, low levels of Apo A-I are associated with increased risk of heart disease and high levels seem to be protective.

Apo B, apo A-I and the apo B/apo A-I ratio have been reported as better predictors of cardiovascular events than LDL-C (8).

Lipid Biomarkers and Cancer Risk

The role of lipid biomarkers in assessing the risk of cancer has not been studied in detail. However, lipid metabolism has now been accepted as a major metabolic pathway involved in many aspects of cancer cell biology (9). In this context, the contribution of dietary factors, such as different types of fatty acids, carbohydrates, and added sugars may be of importance. Hence, it is likely that future therapeutic strategies for cancer will include dietary regimes. Blood lipids and lipoproteins may influence the risk of cancer through insulin resistance, inflammation, and oxidative stress (10).

Some studies have found an inverse association between total cholesterol and the risk of cancer, suggesting that low blood cholesterol may increase cancer risk (11,12, 13). This has led some experts to conclude that too much lowering of cholesterol may be harmful.

However, other studies have found a positive correlation between total cholesterol and the risk of cancer (14).

Very few studies have addressed the association between novel biomarkers such as Apo B-100 and apo A-I and cancer risk.

So it appears that the relationship between lipid biomarkers and cancer risk has not been clarified yet. However, a recently published paper addressing lipid biomarkers and long-term risk of cancer in women may have cast some light on the issue.

Lipids Biomarkers and Cancer Risk in the Women’s Health Study

Chandler and coworkers evaluated the association between plasma lipids and risk of cancer, in a prospective analysis in a large cohort of women aged ≥45, who were free of cancer and heart disease at baseline. The results were recently published on-line in the American Journal of Clinical Nutrition (15).

Breast cancer, colorectal cancer, and lung cancer are the most frequently diagnosed cancers in women. The association between lipid biomarkers and the risk of these cancers was addressed in the study.

Although apo A-I is correlated with HDL-C, and apo B-100 is correlated with total cholesterol and LDL-C, the authors hypothesized that apo A-I and apo B-100 might provide a superior risk prediction for certain cancers than would standard lipid markers.

A total of 15.602 females were followed for a median of 19 years. There were 2.163 incident cancer cases (864 breast cancers, 198 colorectal cancers, and 190 lung cancers).

After multivariable adjustment, women in increasing quartiles of Apo A-I and HDL-C had significantly decreased risk of incident total cancer. The association was slightly attenuated after adjustment for body mass index. Total cholesterol, LDL -C, triglycerides and Apo B-100 were not significantly associated with total cancer incidence.

Women in increasing quartiles of apo B-100 and triglycerides had increased risk of colorectal cancer. HDL-C showed an inverse correlation with the risk of colorectal cancer.

No lipid biomarkers were significantly associated with increased risk of breast cancer.

Women in increasing quartiles of HDL-C and Apo-A1 had significantly decreased risk of lung cancer. After adjustment for BMI, the correlation was only significant for HDL-C.

LDL-C was not significantly associated with risk of total cancer or any site-specific cancers.

The authors of the paper concluded that lifestyle interventions that reduce apo-B 100 or raise HDL-C may be associated with ireduced cancer risk.

The Bottom-Line

Recent evidence suggests that when it comes to cancer, a high-risk lipid profile is somewhat different from that used to predict the risk of heart disease.

Today, LDL-C is a primary target for cardiovascular prevention. However, this biomarker appears pretty useless when it comes to predicting the risk of cancer.

Low HDL-C, on the other hand, seems to be a strong predictor of cancer risk and so are low levels of Apo A-I, the main protein in HDL.

The findings of the recent study by Chandler and coworkers support a possible role of lipid metabolism in the development of cancers. The authors of the paper conclude that the attenuation of the associations between lipids and cancer risk, when adjusted for body mass index, suggests that blood lipids may be involved in the development of cancer through pathophysiologic processes related to obesity.

Low HDL-C and Apo A-I levels are few of the key features of the metabolic syndrome which is also characterized by elevated triglycerides, central obesity, hypertension, and glucose intolerance.

A recent study in the prospective Metabolic Syndrome and Cancer Project suggested a potential role of triglycerides in the development of cancer (16).

Several observational studies suggest that central obesity (17), insulin resistance (18), hyperinsulinemia and low adiponectin (19) levels are associated with increased risk of cancer. Although the mechanisms of this link remain obscure, it is possible that hyperinsulinemia in itself is important in linking insulin resistance to cancer (20). Insulin is a known growth factor and has been put forth as a causative factor in cardiovascular disease. Also, hyperinsulinemia promotes inflammation, which is an established risk factor for the development of cancer (21).

The association between lipid biomarkers and cancer may imply that dietary measures aimed at raising HDL-C and Apo-I, and lowering triglycerides and Apo B-100 may reduce the risk of cancer. However, due to the observational nature of the study, this can only be regarded as a hypothesis.

Although low-fat diets may help to reduce LDL-C, low-carbohydrate diets are more effective in raising HDL-C and reducing inflammation (22, 23). Other lifestyle interventions for cancer prevention such as regular exercise and smoking cessation are also useful in raising HDL- C.

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